1. Technical Field of the Invention
The present invention relates to novel substance P antagonist compositions comprising at least one extract of at least one plant of the Rosaceae family.
This invention also relates to the administration of at least one extract of at least one plant of the Rosaceae family, as the active species or agent for treating disorders associated with an excessive synthesis and/or release of substance P.
The present invention also relates to the use of the subject extracts/compositions for treating sensitive human skins.
2. Description of the Prior Art
There exist, in mammals, polypeptides belonging to the family of tachykinins which induce rapid contractions on the smooth muscle fibers. Among the compounds of this family, representative are .beta.-neurokinin, .alpha.-neurokinin and substance P.
Substance P is a polypeptide chemical component (undecapeptide), produced and released by a nerve ending. The location of substance P is specific to the neurons, both in the central nervous system and in the organs at the periphery. Thus, numerous organs or tissues receive afferences of substance P-bearing neurons; these are, especially, the salivary glands, the stomach, the pancreas, the intestine (in the latter, the distribution of substance P is superposed on the intrinsic Meissner's and Auerbach's nerve plexus), the cardiovascular system, the thyroid gland, the skin, the iris and the ciliary bodies, the bladder and obviously the central and peripheral nervous systems.
By virtue of the ubiquitous distribution of substance P, numerous disorders are associated with an excessive synthesis and/or release of substance P.
Substance P is involved, particularly, in the transmission of pain and in diseases of the central nervous system (for example anxiety, psychoses, neuropathies, neurodegenerative disorders of the type comprising senile dementia of Alzheimer, dementia of AIDs sufferers, Parkinson's disease, Down's syndrome, Korsakoff's syndrome, multiple sclerosis, schizophrenia), in respiratory diseases (such as for example bronchopneumonia) and inflammatory diseases (such as for example rheumatoid arthritis), in allergic syndromes (such as for example asthma, allergic rhinitis, allergic pharyngitis, urticaria, eczematous dermatitis), in gastrointestinal diseases (such as for example ulcers, colitis, Crohn's disease), in skin disorders (such as for example psoriasis, pruriginous diseases, herpes, photodermatosis, atopic dermatitis, contact dermatitis, lichen, prurigo, pruritus, erythema, in particular solar erythema, insect bites), in fibrosis and other collagen maturation disorders (such as for example scleroderma), in cardiovascular disorders, vasospastic disorders (such as for example migraine, Reynaud's disease), in immunological disorders, in disorders of the urinary tract (such as for example incontinence, cystitis), in rheumatic diseases, in some dermatological diseases (such as eczema) and in ophthalmological conditions (such as for example conjunctivitis, uveitis, ocular pruritus, ocular pain, irritations).
The administration of a substance P antagonist is one of the therapeutic alternatives which is effective in all of the aforementioned conditions and afflictions.
By "substance P antagonist" is intended any compound or species capable of inhibiting partially, or even completely, the biological effect of substance P.
In particular, for a substance to be recognized as a substance P antagonist, it should induce a coherent pharmacological response (including or otherwise its attachment to the substance P receptor), especially in one of the following tests:
(a) the antagonist substance should reduce the extravasation of plasma across the vascular wall induced by capsaicin or by an antidromic nerve stimulation, and/or PA1 (b) the antagonist substance should cause inhibition of the contraction of the smooth muscles induced by the administration of substance P. PA1 Tyr-D-Phe Phe D-His Leu Met NH.sub.2 PA1 Tyr represents tyrosine, PA1 D-Phe represents D-phenylalanine PA1 Phe represents phenylalanine PA1 D-His represents D-histidine, PA1 Leu represents leucine PA1 Met represents methionine. PA1 D-NicLys Pro 3-Pal Pro D-Cl.sub.2 Phe Asn D-Trp Phe D-Trp Leu Nle NH.sub.2 PA1 D-NicLys represents D-lysine nicotinate, PA1 Pro represents proline, PA1 3-Pal represents 3-pyridyl-alanine, PA1 D-Cl.sub.2 Phe represents D-dichlorophenylalanine, PA1 Asn represents asparagine, PA1 D-Trp represents D-tryptophan PA1 Phe represents phenylalanine, PA1 Leu represents leucine, PA1 Nle represents norleucine. PA1 (a) the antagonist substance should reduce the vasodilation induced by capsaicin and/or by an antidromic electrical stimulation (applied to an afferent nerve) and/or PA1 (b) the antagonist substance should cause inhibition of the release of CGRP by the sensitive nerve fibers and/or PA1 (c) the antagonist substance should of the contraction of the smooth muscle of the vas deferens induced by CGRP. PA1 D-Arg, [Hyp3, D-Phe7]-bradykinin (NPC567), PA1 [Thi 5, 8, D-Phe7]-bradykinin, D-Arg, [Hyp3, Thi5,8, PA1 D-Phe7]-bradykinin, PA1 N-.alpha.-adamantaneacetyl-D-Arg, [Hyp3, Thi5,8, D-Phe7]-bradykinin, PA1 des-Arg9, [Leu8]-bradykinin, PA1 P-guanidobenzoyl, [Hyp3,Thi5,D-Tic7,Oic8]-bradykinin (S 16118), PA1 D-Arg, [Hyp3, Thi5, D-Tic7,Oic8]-bradykinin (HOE 140), PA1 D-Arg, [Hyp3, D-Hype (trans-propyl)7, Oic8]-bradykinin (NPC 17731) PA1 (a) have an affinity for the receptors specific for these compounds; PA1 (b) have a histamine, cytokine or TNF-.alpha. receptor antagonist pharmacological activity, namely, induce a coherent pharmacological response in at least one of the following tests: PA1 (a) inhibition of the release of histamine by mastocytes stimulated by the compound 48/80 or stimulated by a calcium ionophore (A23 187) PA1 (b) inhibition of the release of cytokines or TNF-.alpha. by monocytes (U937 cells) differentiated by a phorbol ester (PMA). PA1 (a) agents modulating skin pigmentation and/or proliferation and/or differentiation such as retinoic acid and isomers hereof, retinol and esters thereof, vitamin D and derivatives thereof, estrogens such as estradiol, kojic acid or hydroquinone; PA1 (b) antibacterial agents such as clindamycin phosphate, erythromycin or antibiotics of the class of tetracyclines; PA1 (c) antiparasitic agents, in particular metronidazole, crotamiton or pyrethrinoids; PA1 (d) antifungal agents, in particular the compounds belonging to the class of imidazoles such as econazole, ketoconazole or miconazole or their salts, polyene compounds, such as amphotericin B, compounds of the family of allylamines, such as terbinafin, or alternatively octopirox; PA1 (e) antiviral agents such as acyclovir; PA1 (f) steroidal anti-inflammatory agents, such as hydrocortisone, betamethasone valerate, clobetasol propionate, or nonsteroidal anti-inflammatory agents such as ibuprofen and its salts, diclofenac and its salts, acetylsalicylic acid, acetaminophen or glycyrrhetinic acid; PA1 (g) anaesthetic agents such as lidocaine hydrochloride and derivatives thereof; PA1 (h) antipruriginous agents such as thenaldine, trimeprazine or cyproheptadine; PA1 (i) keratolytic agents such as alpha- and beta-hydroxycarboxylic or beta-ketocarboxylic acids, their salts, amides or esters and more particularly hydroxy acids such as glycolic acid, lactic acid, salicylic acid, citric acid and in general fruit acids, and 5-n-octanylsalicylic acid; PA1 (j) anti-free radical agents, such as alpha-tocopherol or its esters, superoxide dismutases, some metal chelators or ascorbic acid and its esters; PA1 (k) antiseborrhoeic agents such as progesterone; PA1 (l) antidandruff agents such as octopirox or zinc pyrithione; PA1 (m) antiacne agents such as retinoic acid or benzoyl peroxide; PA1 (n) plant extracts or extracts of microbial origin.
To date, substance P antagonists have been administered to treat the disorders indicated above. Compare, for example, U.S. Pat. No. 4,472,305, U.S. Pat. No. 4,839,465, EP-A-101929, EP-A-333174, EP-A-336230, EP-A-394989, EP-A-443132, EP-A-498069, EP-A-515681, EP-A-517589, WO-A-92/22569, GB-A-2216529, EP-A-360390, EP-A-429366, EP-A-430771, EP-A-499313, EP-A-514273, EP-A-514274, EP-A-514275, EP-A-514276, EP-A-520555, EP-A-528495, EP-A-532456, EP-A-545478, EP-A-558156, WO-A-90/05525, WO-A-90/05729, WO-A-91/18878, WO-A-91/18899, WO-A-92/12151, WO-A-92/15585, WO-A-92/17449, WO-A-92/20676, WO-A-93/00330, WO-A-93/00331, WO-A-93/01159, WO-A-93/01169, WO-A-93/01170, WO-A-93/06099, WO-A-93/09116, EP-A-522808 and WO-A-93/01165.
However, the aforesaid prior art neither discloses nor suggests that an extract of at least one plant of the Rosaceae family elicits a substance P-antagonizing activity as defined above and therefore would be useful as an active ingredient for treating the disorders indicated above.
Plants of the Rosaceae family are principally used for their aromatic and ornamental properties.
In the prior art, plants of the Rosaceae family have been utilized in compositions for the treatment of urogenital diseases (FR-76/36295), in lightening cosmetic compositions (JP-08208451) or in compositions for protecting against ultraviolet radiation (EP-A-781544), for the preparation of antioxidant compounds (EP-A-94/401669), or, alternatively, for the preparation of antimicrobial and/or insecticidal compounds for the protection of plants (DE-4,327,792).
Heretofore, the substance P-antagonizing activity of at least one plant of the Rosaceae family was unknown.